The invention relates to hydrophilic membranes which are supplemented or treated with a non-ionic surfactant and processes for preparing such membranes. The membranes are particularly suitable for plasma separation or for haemodialysis or haemodiafiltration, but can also advantageously be used in other applications. Accordingly, the invention is further directed to the use of such membranes for plasma separation, plasma filtration, micro filtration, plasma therapy, haemodialysis, haemodiafiltration or cell filtration applications, respectively. The coated hydrophilic membranes show excellent biocompatibility, such as reduced platelet drop and decreased TAT levels.
The invention particularly relates to the treatment of hydrophilic micro porous membranes which will preferably be used for plasma separation. Micro porous membranes have an average pore size of from about 0.05 μm to about 10.0 μm, but generally the selective pore size will not exceed 1 to 2 μm. Plasma separation or apheresis is a medical technology in which the blood of a donor or patient is separated into the plasma, i.e. the cell free component in blood, and the blood cells. Plasma separation may be conducted for several reasons. In the therapeutical plasmapheresis the separated plasma of a patient's blood is discarded and replaced by a substitute solution or by donor plasma, and is reinfused into the patient. This approach is useful in the treatment of several diseases and disorders. For example, in immunological diseases the plasmapheresis is useful to exchange antibodies, antigens, immune complexes or immune globulins. In non-immunological diseases the plasmapheresis allows for the depletion of metabolites, degradation products, as well as endogenous and exogenous toxins. In a variant of therapeutical plasmapheresis, plasma fractionation, the separated plasma of a patient's blood undergoes a second stage of further separation into high molecular and low molecular plasma fractions. The high molecular fraction is discarded, and the low molecular fraction of the plasma and the cellular components of the blood are reinfused into the patient. In another application, called plasma donation, the separated blood plasma from healthy donors is used for therapeutical plasma exchange or for the isolation of plasma components for pharmaceutical purposes.
The separation of whole blood into plasma and cellular components can be achieved either by centrifugation or by passing the blood through a plasma separation membrane. During the development of plasmapheresis, discontinuous centrifuges have been used first, which have then, at the beginning of the 70s, been replaced by continuous centrifugation systems. Centrifugation techniques have the advantage of being fast and cost effective; however, they often suffer from leaving impurities of cells or cell debris in the separated plasma. At the end of the 70s, the first membrane systems have been introduced for the plasmapheresis to overcome the disadvantages of centrifugation systems.
While being related to it, the requirements of plasma separation membranes are quite distinct from the requirements of dialysis membranes. Plasma separation uses the effect of separation by filtration, whereas dialysis rather uses osmosis and diffusion.
The sieving coefficient determines how much of a compound will be eliminated by a filtration process. The sieving coefficient is defined as the ratio of the concentration of a compound in the filtrate to the concentration of this compound in the blood. A sieving coefficient of “0” means, that the compound can not pass the membrane. A sieving coefficient of “1” means that 100% of the compound can pass the membrane. For the design of plasma separation membranes it is desirable that the whole spectrum of plasma proteins can pass the filtration membrane whereas the cellular components are completely retained.
The requirements of a plasma separation membrane for plasmapheresis can be summarized by the following characteristics: (1) high permeability or high sieving coefficient for the whole spectrum of plasma proteins and lipoproteins; (2) high surface porosity and total porosity of the membrane to achieve high filtration performance; (3) a hydrophilic, spontaneously wettable membrane structure; (4) low fouling properties for long term stable filtration; (5) low protein adsorption; (6) smooth surface in contact with blood; (7) low or no tendency to haemolysis during blood processing; (8) constant sieving properties and filtration behaviour over the whole treatment period; (9) high biocompatibility, no complement activation, low thrombogenicity; (10) mechanical stability; (11) sterilizability by steam, gamma radiation and/or ETO; (12) low amount of extractables.
Membranes which turned out to be especially suitable with regard to the above characteristics have been described in detail in European Patent Application No. 06116781.3 and European Patent Application No. 06116786.2, both of which are included herein by reference.
The material of the membranes according to the present invention is a polymer composition with relatively high hydrophilic properties. “Hydrophilic” membranes, in contrast to “hydrophobic” membranes can be defined, in accordance with the present invention, by their ability to be spontaneously water wettable without wetting aids. A membrane, independent of its shape, is called readily or spontaneously water wettable if it is wetted by water virtually spotlessly. When, for example, a piece of a flat membrane (50 mm in diameter) is stamped out of a dry test membrane and placed on water of 20° C. After one minute a visual check is made whether the membrane was spotlessly wetted by water. Hydrophilic membranes can alternatively be described as having a low contact angle with the applied water. Indeed, when a drop of water is placed on a hydrophilic, spontaneously wettable membrane or medium formed there from, the drop of liquid penetrates and wets the membrane, effectively providing a zero angle of contact therewith.
It is generally advantageous to use hydrophilic membranes in plasma separation applications, as such membranes show better performance with regard to filtration properties and have a reduced tendency to adsorb blood components and thus show a better blood compatibility. The above mentioned membranes belong to this group of advantageous, hydrophilic membranes.
Even though said membranes already show all of the characteristics which are needed for a membrane which is to be used for plasmapheresis, there are aspects which deserve improvement to achieve an even better performance. Such aspects are especially the improvement of thrombogenicity and a reduced interaction with blood components which can still be observed to a certain extend with hydrophilic membranes.
The invention is also directed to semipermeable hydrophilic membranes for haemodialysis or haemodiafiltration which are treated or supplemented with a non-ionic surfactant for improving the biocompatibility of such membranes, especially their thrombogenicity.
The expression “non-ionic surfactants” as used herein refers to a surfactant which does not dissociate is called a non-ionic surfactant. The molecules are uncharged. The hydrophilic group of non-ionic surfactants is a polymerized alkylene oxide, preferably ethylene oxide (a water soluble polyether with 10 to 100 units length typically). Non-ionic surfactants include alcohol ethoxylates, alkylphenol ethoxylates, phenol ethoxylates, amide ethoxylates, glyceride ethoxylates (soya bean oil and castor oil ethoxylates), fatty acid ethoxylates, and fatty amine ethoxylates. Other significant non-ionic surfactants are the alkyl glycosides in which the hydrophilic groups are sugars (polysaccharides). Preferred non-ionic surfactants in the context of the present invention are polyoxyethylene sorbitan surfactants.
The invention is also directed to a method of treating semipermeable hydrophilic membranes for haemodialysis or haemodiafiltration with a non-ionic surfactant, preferably polyoxyethylene sorbitan surfactants, more preferably with polyoxyethylene sorbitan monolaurate (polysorbate 20 or Tween® 20).
Attempts to improve the performance of hydrophobic membranes are well known in the prior art, as such membranes generally suffer from low filtration property and a high tendency to adsorb blood components.
In EP 0 188 104 A2 methods are described for improving the wettability of a porous, hydrophobic polymer surface, e.g. made from polypropylene, polyester, polyethylene and/or polyurethane, by spraying or dipping the polymer surface into a preferably non-aqueous solution of e.g. polysorbate 20, 40, 60 or 80, directly followed by drying. The concentration of polysorbate in the solution used lies in the range of about 0.1-0.5% w/v.
In JP 61-133105, methods are described for improving the permeability and wettability of a hydrophobic porous membrane, preferably made of polyethylene, by immersing the membrane in an aqueous solution containing 0.001-10% (w/w) of e.g. polyoxyethylene sorbitan fatty acid ester for a certain time, followed by drying.
In JP 63-277251 discloses methods for improving water permeability of porous, hydrophobic polysulfone-based membranes having a pore-size of 0.01-5 μm by immersing the membrane in e.g. an aqueous solution containing 0.001-15% w/w of e.g. a polyoxyethylene sorbitane alkyl ester surfactant (monolaurate) for a certain time, followed by high-frequency drying.
EP 1 334 763 B1 also claims porous, hydrophobic polysulfone-based membranes which are coated on the surface with 0.002-25% w/w of a polyoxyethylene sorbitane surfactant, such as have been described already in JP 63-277251. The only difference to JP 63-277251 lies in the method of applying the surfactant as it additionally includes a step of rinsing the membrane to remove excess surfactant from the membrane.
However, none of the above-mentioned references, nor any other prior art mentions that not only hydrophobic membranes can be improved by an additional treatment with a non-ionic surfactant, but that, surprisingly, also hydrophilic membranes can be improved by such treatment. This is astonishing since one would assume that hydrophilic membranes do not require an improvement of wettability or water permeability like it is obviously the case with hydrophobic membranes. In fact, it is already surprising that hydrophilic membranes can be coated with a polyoxyethylene sorbitan at all to an extent that makes a difference to the biocompatibility of such hydrophilic membrane.